👤 Olga Balaguer

Nowadays, there is an unmet need for reliable and minimally-invasive diagnosis tools capable of detecting Alzheimer's disease at early stages. Such tools could significantly reduce the reliance on confirmatory tests that are invasive and costly, such as cerebrospinal fluid (CSF) biomarkers and neuroimaging. The aim of this study is to validate previously developed diagnosis tools (multivariate models and plasma p-Tau217 levels) in three independents cohorts. For this, a cohort was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) including some variables (age, Apolipoprotein E (ApoE) genotype, plasma p-Tau217, CSF biomarkers) (n = 113); and two cohorts from cognitive disorders units (Hospital Universitari i Politècnic La Fe (HUiPLaFe, n = 163), Hospital Doctor Peset (n = 31)), whose plasma samples were analysed to determine plasma p-Tau217, and to evaluate the previous diagnosis tools performance. For the cohort from HUiPLaFe, the multivariate model (plasma p-Tau217, age, ApoE genotype) showed a sensitivity of 94.9% and a specificity of 88.2%; for the cohort from Hospital Doctor Peset, the sensitivity was 100% and specificity 80%; for the ADNI cohort, sensitivity was 89.5% and specificity 39.5%. Regarding the plasma p-Tau217 levels, the results were satisfactory for the cognitive disorders units; while ADNI cohort showed very low specificity. In conclusion, the multivariate model was clinically validated in independent cohorts from clinical units, representing its first step for implementation. Show less

Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARalpha, PPARgamma, and LXRalpha. We show it activates the ligand-binding domain of both PPARalpha and PPARgamma, while inhibiting LXRalpha in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRalpha, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARalpha co-activator, PGC1alpha. The flavonoid activates PPAR response element (PPRE) while suppressing LXRalpha response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRalpha-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRalpha inhibitor. Show less